Icosanoids are potent biologic mediators derived from a specifically designated pool of fatty acids known as icosanoid-precursor fatty acids. Inhibition of icosanoid production by aspirin has been shown to reduce inflammation and the risk of thrombosis leading to stroke and myocardial infarction. For the last 5 years our laboratory has been investigating the molecular mechanisms by which arachidonate, the principal icosanoid precursor fatty acid, is converted to icosanoids, with the intention of identifying new regulatory steps which might be susceptible to pharmacologic intervention. In an effort to continue this work, this proposal also describes experiments intended to increase our understanding of the molecular events in the conversion of arachidonate and other icosanoid-precursor fatty acids to icosanoids. However, where our previous work focused exclusively on cellular fatty acid metabolism, the goals of the proposed work are to determine 1) the molecular mechanisms by which fatty acids are delivered to cells from triacylglycerol, phospholipids, and cholesterol esters in lipoproteins and from the nonesterified fatty acid pool bound to albumin and 2) how the particular route of delivery of fatty acid to cells effects its distribution within membranes of the cell and its metabolic fate inside the cells. Our first major objective is to determine which fatty acid-containing moieties within lipoproteins containing icosanoid precursor fatty acids actually deliver these fatty acids to cells (endothelial cells, platelets, and Hep G2 cells). Within this first objective, we will compare delivery of fatty acids to cells from the different lipoprotein moieties vs free fatty acid bound to albumin. Our second major objective is to determine whether the fate of icosanoid precursor fatty acids in cells, in terms of subcellular distribution (in Hep G2 cells), availability for icosanoid production (by endothelial cells and platelets), or packaging into newly synthesized lipoproteins (by Hep G2 cells), is dependent on the moiety which delivers the fatty acid to the cell. This series of aims, a logical extension of our previous work, will provide missing details on the molecular events by which icosanoid precursor fatty acids are transported in the plasma and delivered to cells.
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